Kainate-Mediated Excitotoxicity Induces Neuronal Death in the Rat Spinal Cord In Vitro via a PARP-1 Dependent Cell Death Pathway (Parthanatos)

Abstract Glioblastoma (GBM) is the most common aggressive form of brain cancer with overall dismal prognosis (10–12 months) despite all current multimodal treatments. Previously we identified adipocyte enhancer binding protein 1 (AEBP1) as a differentially regulated gene in GBM. On probing the role of AEBP1 over expression in glioblastoma, we found that both cellular proliferation and survival were affected upon AEBP1 silencing in glioma cells, resulting in cell death. In the present study we report that the classical caspase pathway components are not activated in cell death induced by AEBP1 down regulation in PTEN-deficient (U87MG and U138MG) cells. PARP-1 was not cleaved but over-activated under AEBP1 down regulation which leads to the synthesis of PAR in the nucleus triggering the release of AIF from the mitochondria. Subsequently, AIF translocates to the nucleus along with MIF causing chromatinolysis. AEBP1 positively regulates PI3KinaseCβ by the binding to AE-1 binding element in the PI3KinaseCβ promoter. Loss of PI3KinaseCβ expression under AEBP1 depleted condition leads to excessive DNA damage and activation of PARP-1. Furthermore, over expression of PIK3CB (in trans) in U138MG cells prevents DNA damage in these AEBP1 depleted cells. On the contrary, AEBP1 down regulation induces caspase-dependent cell death in PTEN-proficient (LN18 and LN229) cells. Ectopic expression of wild-type PTEN in PTEN-deficient U138MG cells results in the activation of canonical caspase and Akt dependent cell death. Collectively, our findings define AEBP1 as a potential oncogenic driver in glioma, with potential implications for therapeutic intervention.

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Microarray analysis of expression of cell death-associated genes in rat spinal cord cells exposed to cyclic tensile stresses in vitro

BMC Neuroscience ◽

10.1186/1471-2202-11-84 ◽

2010 ◽

Vol 11 (1) ◽

Cited By ~ 10

Author(s):

Kenzo Uchida ◽

Hideaki Nakajima ◽

Takayuki Hirai ◽

Takafumi Yayama ◽

Ke-Bing Chen ◽

...

Keyword(s):

Spinal Cord ◽

Cell Death ◽

Microarray Analysis ◽

Rat Spinal Cord ◽

Tensile Stresses

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Photocytotoxicity of Hypocrellin B (HB) was Enhanced by Liposomalization in Vitro

International Journal of Toxicology ◽

10.1177/1091581810394548 ◽

2011 ◽

Vol 30 (2) ◽

pp. 174-180 ◽

Cited By ~ 8

Author(s):

Zhixiang Zhou ◽

Lina Zhang ◽

Huimin Liu ◽

Qi Zhang ◽

Boya Liu ◽

...

Keyword(s):

Cell Death ◽

Confocal Microscopy ◽

Cellular Uptake ◽

Hela Cells ◽

Type Ii ◽

Cell Death Pathway ◽

Hypocrellin B ◽

Phosphatidylcholine Liposome ◽

Dependent Cell

Hypocrellin B (HB) was encapsulated into a phosphatidylcholine liposome. Encapsulation of HB into liposomes not only improved the delivery of this photosensitizer but also increased its photodynamic efficacy compared to free HB molecules. Liposomal HB showed a higher cellular uptake than free HB as measured by confocal microscopy and was internalized into cultured HeLa cells by caveolar endocytosis, which was lipid-raft-dependent. Cell viability measurements demonstrated that liposomal HB was more phototoxic to HeLa cells than free HB as a result of the higher concentration of intracellular HB delivered by the liposomal formulation. The encapsulation of HB influenced the cell death pathway by an increased rate of necrotic cells after irradiation versus free HB, and a Type II (singlet oxygen) mechanism was responsible for the photocytotoxicity.

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Simvastatin protects ischemic spinal cord injury from cell death and cytotoxicity through decreasing oxidative stress: in vitro primary cultured rat spinal cord model under oxygen and glucose deprivation-reoxygenation conditions

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-017-0536-9 ◽

2017 ◽

Vol 12 (1) ◽

Cited By ~ 14

Author(s):

Hye-Min Sohn ◽

Jin-Young Hwang ◽

Jung-Hee Ryu ◽

Jinhee Kim ◽

Seongjoo Park ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Death ◽

Glucose Deprivation ◽

Rat Spinal Cord ◽

Oxygen And Glucose Deprivation ◽

Cord Injury ◽

Ischemic Spinal Cord Injury

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The in vitro neonatal rat spinal cord preparation: a new insight into mammalian locomotor mechanisms

Journal of Comparative Physiology A ◽

10.1007/s00359-004-0499-2 ◽

2004 ◽

Vol 190 (5) ◽

pp. 343-357 ◽

Cited By ~ 35

Author(s):

F. Clarac ◽

E. Pearlstein ◽

J. F. Pflieger ◽

L. Vinay

Keyword(s):

Spinal Cord ◽

Neonatal Rat ◽

Rat Spinal Cord ◽

Insight Into

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DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

Nature Communications ◽

10.1038/s41467-021-22622-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lama Tarayrah-Ibraheim ◽

Elital Chass Maurice ◽

Guy Hadary ◽

Sharon Ben-Hur ◽

Alina Kolpakova ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

Germ Cells ◽

Nuclear Translocation ◽

Primordial Germ Cells ◽

Nuclear Accumulation ◽

Dependent Manner ◽

Dnase Ii ◽

Cell Death Pathway ◽

Parp 1

AbstractDuring Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.

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Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽

10.3390/biomedicines9040376 ◽

2021 ◽

Vol 9 (4) ◽

pp. 376

Author(s):

Chantal B. Lucini ◽

Ralf J. Braun

Keyword(s):

Cell Death ◽

Oxygen Species ◽

In Vivo Models ◽

Dependent Cell ◽

Cell Death Mechanisms ◽

Sting Pathway ◽

Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

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The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers

Genes ◽

10.3390/genes10060453 ◽

2019 ◽

Vol 10 (6) ◽

pp. 453 ◽

Cited By ~ 8

Author(s):

Arianna Tolone ◽

Soumaya Belhadj ◽

Andreas Rentsch ◽

Frank Schwede ◽

François Paquet-Durand

Keyword(s):

Cell Death ◽

Gene Mutations ◽

Interdisciplinary Cooperation ◽

Response To Treatment ◽

Common Denominator ◽

Photoreceptor Degeneration ◽

Diverse Range ◽

Cell Death Pathway ◽

Cgmp Signaling ◽

Dependent Cell

Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.

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